MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma
Abstract: In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment decisions remains unclear. In a phase 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by...
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Elsevier
2025-02-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S247395292400675X |
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| author | Manisha Bhutani Myra Robinson David Foureau Shebli Atrash Barry Paul Fei Guo Jason M. Grayson Anna Ivanina-Foureau Mauricio Pineda-Roman Cindy Varga Reed Friend Christopher J. Ferreri Xhevahire Begic Sarah Norek Tiffany Drennan Michelle B. Anderson James T. Symanowski Peter M. Voorhees Saad Z. Usmani |
| author_facet | Manisha Bhutani Myra Robinson David Foureau Shebli Atrash Barry Paul Fei Guo Jason M. Grayson Anna Ivanina-Foureau Mauricio Pineda-Roman Cindy Varga Reed Friend Christopher J. Ferreri Xhevahire Begic Sarah Norek Tiffany Drennan Michelle B. Anderson James T. Symanowski Peter M. Voorhees Saad Z. Usmani |
| author_sort | Manisha Bhutani |
| collection | DOAJ |
| description | Abstract: In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment decisions remains unclear. In a phase 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by a next-generation sequencing–based MRD-adapted strategy. The primary outcome was complete response (CR) and stringent CR (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR after induction (P = .375), with MRD-negative rates of 59% (10−5) and 41% (10−6). Patients who were MRD-negative (n = 24, group A) received lenalidomide maintenance, showing sustained MRD negativity in 14 of 18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n = 8, group B) underwent autologous stem cell transplantation, with 62.5% converting to MRD-negative at 10−5 (37.5% at 10−6) posttransplant. MRD-positive, transplant-ineligible patients (n = 4, group C) received KRd consolidation. Best MRD-negative rates improved to 77% (10−5) and 72% (10−6). No new safety concerns were identified for Dara-KRd. With a median follow-up of 30.1 months, 3, 2, and 1 patient(s) in groups A, B, and C, respectively, have progressed or died. We observed that Dara-KRd strongly activated memory T cells, which was associated with an MRD-negative state post induction. Although the primary outcome was not met, Dara-KRd induction in NDMM achieved high ≥CR and MRD-negative rates without new safety concerns. The post induction MRD-adapted strategy deepened responses in MRD-positive patients and maintained durable MRD control in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT04113018. |
| format | Article |
| id | doaj-art-f5ca813ef37645bd97c540c2d644012c |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Blood Advances |
| spelling | doaj-art-f5ca813ef37645bd97c540c2d644012c2025-01-30T05:14:48ZengElsevierBlood Advances2473-95292025-02-0193507519MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myelomaManisha Bhutani0Myra Robinson1David Foureau2Shebli Atrash3Barry Paul4Fei Guo5Jason M. Grayson6Anna Ivanina-Foureau7Mauricio Pineda-Roman8Cindy Varga9Reed Friend10Christopher J. Ferreri11Xhevahire Begic12Sarah Norek13Tiffany Drennan14Michelle B. Anderson15James T. Symanowski16Peter M. Voorhees17Saad Z. Usmani18Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC; Correspondence: Manisha Bhutani, Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, 1021 Morehead Medical Dr, Building 2, Charlotte, NC 28204;Department of Biostatistics and Data Sciences, Atrium Health Levine Cancer Institute, Charlotte, NCDepartment of Internal Medicine, Section of Hematology and Oncology, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Internal Medicine, Section of Hematology and Oncology, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NCDepartment of Internal Medicine, Section of Hematology and Oncology, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NCClinical Trials Office, Wake Forest Baptist Comprehensive Cancer Center, Atrium Health Levine Cancer, Charlotte, NCClinical Trials Office, Wake Forest Baptist Comprehensive Cancer Center, Atrium Health Levine Cancer, Charlotte, NCClinical Trials Office, Wake Forest Baptist Comprehensive Cancer Center, Atrium Health Levine Cancer, Charlotte, NCDepartment of Biostatistics and Data Sciences, Atrium Health Levine Cancer Institute, Charlotte, NCDepartment of Biostatistics and Data Sciences, Atrium Health Levine Cancer Institute, Charlotte, NCDepartment of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC; Peter M. Voorhees, Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, 1021 Morehead Medical Dr, Building 2, Charlotte, NC 28204;Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Saad Z. Usmani, Myeloma Service, Memorial Sloan Kettering Cancer Center, 530 East 74th St, Room 20-228, New York, NY 10021;Abstract: In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment decisions remains unclear. In a phase 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by a next-generation sequencing–based MRD-adapted strategy. The primary outcome was complete response (CR) and stringent CR (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR after induction (P = .375), with MRD-negative rates of 59% (10−5) and 41% (10−6). Patients who were MRD-negative (n = 24, group A) received lenalidomide maintenance, showing sustained MRD negativity in 14 of 18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n = 8, group B) underwent autologous stem cell transplantation, with 62.5% converting to MRD-negative at 10−5 (37.5% at 10−6) posttransplant. MRD-positive, transplant-ineligible patients (n = 4, group C) received KRd consolidation. Best MRD-negative rates improved to 77% (10−5) and 72% (10−6). No new safety concerns were identified for Dara-KRd. With a median follow-up of 30.1 months, 3, 2, and 1 patient(s) in groups A, B, and C, respectively, have progressed or died. We observed that Dara-KRd strongly activated memory T cells, which was associated with an MRD-negative state post induction. Although the primary outcome was not met, Dara-KRd induction in NDMM achieved high ≥CR and MRD-negative rates without new safety concerns. The post induction MRD-adapted strategy deepened responses in MRD-positive patients and maintained durable MRD control in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT04113018.http://www.sciencedirect.com/science/article/pii/S247395292400675X |
| spellingShingle | Manisha Bhutani Myra Robinson David Foureau Shebli Atrash Barry Paul Fei Guo Jason M. Grayson Anna Ivanina-Foureau Mauricio Pineda-Roman Cindy Varga Reed Friend Christopher J. Ferreri Xhevahire Begic Sarah Norek Tiffany Drennan Michelle B. Anderson James T. Symanowski Peter M. Voorhees Saad Z. Usmani MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma Blood Advances |
| title | MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma |
| title_full | MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma |
| title_fullStr | MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma |
| title_full_unstemmed | MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma |
| title_short | MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma |
| title_sort | mrd driven phase 2 study of daratumumab carfilzomib lenalidomide and dexamethasone in newly diagnosed multiple myeloma |
| url | http://www.sciencedirect.com/science/article/pii/S247395292400675X |
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